Resolvins

TLDR

Aspirin acetylates COX‑2, enabling synthesis of R‑containing anti‑inflammatory precursors. The study reports that lipidomic analysis of resolution‑phase exudates from ASA‑treated mice and DHA reveals a novel family of bioactive 17R‑hydroxy di‑ and tri‑hydroxy docosanoids called resolvins. These pathways convert omega‑3 DHA and EPA via COX‑2/ASA to 17R‑hydroxy docosanoids that enhance pro‑resolution status. Resolvins derived from ASA‑stimulated DHA inhibit microglial cytokine expression and markedly reduce inflammation in vivo, showing that aspirin‑mediated conversion of DHA to 17R‑hydroxy docosanoids potently regulates leukocyte, vascular, and neural inflammation.

Abstract

Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA–derived 17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC50 ∼50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40–80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.